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Progestins in cervical mucus can be efficiently retrieved from ophthalmic sponges. Fifty and 500 ng of progesterone and progestins were spiked onto ophthalmic sponges and eluted with 100% methanol. Progesterone (A) and progestin (B-D) values were measured via LC-MS/MS methodologies. Data are representative of 2 independent experiments. Student t tests were performed to compare input control levels to levels eluted from ophthalmic sponges. No statistically significant differences were noted between any groups. https://doi.org/10.1371/journal.pone.0214152.g002
Source publication
Progestin-only long-acting reversible contraceptives (LARCs) are increasingly popular among women seeking contraception; however, recent epidemiological studies suggest that systemically administered medroxyprogesterone acetate (MPA) may increase HIV acquisition. In order to determine the exact mechanisms underlying increases in transmission specif...
Contexts in source publication
Context 1
... were eluted from sponges using 100% methanol, as determined in Fig 1. Progesterone and progestin levels were then quantified in eluted and unabsorbed control samples in methanol using LC-MS/MS (Fig 2). No statistical differences were seen between measured concentrations of unabsorbed stock controls and levels measured in eluted sponge samples for any of the hormones measured (Fig 2A-2D). ...
Context 2
... were eluted from sponges using 100% methanol, as determined in Fig 1. Progesterone and progestin levels were then quantified in eluted and unabsorbed control samples in methanol using LC-MS/MS (Fig 2). No statistical differences were seen between measured concentrations of unabsorbed stock controls and levels measured in eluted sponge samples for any of the hormones measured (Fig 2A-2D). 100% methanol was therefore used to elute and quantify progestins from cervical sponges collected from our patient cohort. ...
Similar publications
Background:
Observational and laboratory studies suggest that some hormonal contraceptive methods, particularly intramuscular depot medroxyprogesterone acetate (DMPA-IM), might increase women's susceptibility to HIV acquisition. We aimed to compare DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant among African women...
Citations
... Endometrium thickness was insigni cantly different among the four groups at 1st month till 6th month. Figure 3 Discussion LARCs are increasingly prevalent among females looking for contraception [15]. Progestogens are the primary active ingredient in hormonal contraception due to their three primary modes of action. ...
Background
Progestogen-only contraceptives are presented as injections, implants, oral formulations, hormone-releasing intrauterine methods, and emergency contraceptives. This study assessed the effect of different progesterone-containing contraceptive methods on safety and endogenous progesterone level.
Methods
This prospective cohort study included 80 healthy fertile females aged between 20 and 35 years with normal menstrual history who had at least one offspring after spontaneous pregnancy. Subjects were divided into four equal groups according to the contraceptive method: group D (Depo-Provera®) used the injectable progesterone of 150 mg every 90 days or 3 months, group I contained 68 mg of etonogestrel implant formerly known as Implanon, group N: used norgestrel (Ovrette®), (each pill contains 0.075 mg of norgestrel) once daily, and group M: used intrauterine device (IUD) (Mirena) containing 52 mg of levonorgestrel.
Results
Group M had a higher endogenous progesterone level compared to those who used other contraceptives with a normal follicle size. Incidence of amenorrhea was significantly lower in group M (20%) than in group D (75%), group I (65%), and group N (70%), with an insignificant difference among the other three groups. Continuation rate had significantly increased in group M than in the other three groups after 6 months. Efficacy was insignificantly different among the four groups.
Conclusion
Mirena had low systemic absorption of exogenous progesterone, so it had less effect on endogenous progesterone with better follicle size and low incidence of side effects (amenorrhea) compared to other contraceptives containing progesterone.
... Table 5 Endometrium thickness was insigni cantly different among the four groups at 1 st month till 6 th month. Figure 3 Discussion LARCs are increasingly prevalent among females looking for contraception [15] . Progestogens are the primary active ingredient in hormonal contraception, as they have essentially three modes of action, their structure and the action pro le are different, they show a multifocal form of action in contraception. ...
Background
Progestogen-only’ contraceptives are presented as injections, implants, oral formulations, hormone-releasing intrauterine methods, and emergency contraceptives. The research designed to assess the influence of progesterone in different progesterone containing contraceptive methods on endogenous progesterone level and ovulation rate.
Methods
This prospective cohort observational research was involved 80 healthy fertile females aged 20–35 years with normal menstrual history and had at least one offspring after spontaneous pregnancy. Subjects were classified into 4 equal groups according to contraceptive method: D group: used the injectable progesterone of 150 mg every 90 days or 3 months (Depo-Provera), I group: etonogestrel implant which contains 68 mg of etonogestrel, formerly known as Implanon, N group: used norgestrel (Ovrette, with each pill containing 0.075 mg of norgestrel), M group: used IUD (Mirena) containing 52 mg of levonorgestrel.
Results
women who in M group had higher endogenous progesterone level compared to those who used other contraceptives containing with normal follicle growth and normal follicle size. Incidence of amenorrhea was significantly decreased in M group 20% than D group 75%, I group ,65%, N group 70% and there was an insignificant difference among other three groups. Continuation rate was significantly increased in M group than other three groups after 3 months and 6 months
Conclusion
Mirena had low systemic absorption of exogenous progesterone so, it had low effect on endogenous progesterone and ovulation rate with low incidence of side effects compared to other contraceptives containing progesterone. Therefore, Mirena is an effective and safe method as contraceptive and can be used with women who had complication with using progesterone containing contraceptive methods in the study.
... Table 5 Endometrium thickness was insigni cantly different among the four groups at 1 st month till 6 th month. Figure 3 Discussion LARCs are increasingly prevalent among females looking for contraception [15] . Progestogens are the primary active ingredient in hormonal contraception, as they have essentially three modes of action, their structure and the action pro le are different, they show a multifocal form of action in contraception. ...
Background: Progestogen-only’ contraceptives are presented as injections, implants, oral formulations, hormone-releasing intrauterine methods, and emergency contraceptives. The research designed to assess the effect of different progesterone containing contraceptive methods on safety and endogenous progesterone level.
Methods: This prospective cohort study was involved 80 healthy fertile females aged 20-35 years with normal menstrual history and had at least one offspring after spontaneous pregnancy. Subjects were classified into four equal groups according to contraceptive method: group D(Depo-Provera®): used the injectable progesterone of 150 mg every 90 days or 3 months, group I: contains 68 mg of etonogestrel implant formerly known as Implanon, group N: used norgestrel (Ovrette®), (each pill containing 0.075 mg of norgestrel) once daily, and group M: used IUD (Mirena) containing 52 mg of levonorgestrel.
Results: Group M had higher endogenous progesterone level compared to those who used other contraceptives containing with normal follicle size. Incidence of amenorrhea was significantly lower in group M (20%) than group D (75%), group I (65%), and group N (70%) with an insignificant difference among the other three groups. Continuation rate was significantly higher in group M than other three groups after 6 months. Efficacy was insignificantly different among the four groups.
Conclusion: Mirena had low systemic absorption of exogenous progesterone so, it had less effect on endogenous progesterone with better follicle size and low incidence of side effects (amenorrhea) compared to other contraceptives containing progesterone.
... When administered as a contraceptive MPA has a dynamic concentration profile. Shortly after injection of 150 mg intramuscular MPA, serum concentration peaks at around 4.5-65 nM between 5 and 20 days 34 , before decreasing steadily and plateauing around 2.5 nM [35][36][37] 58 . To ensure that our study has biological relevance, we used concentrations of MPA (0.1, 1, 10, & 100 nM) that encompass the serum levels found in women using MPA as a contraceptive. ...
... This observation is consistent with clinical studies that suggest LNG use does not alter susceptibility to HIV transmission in women 17 . Importantly, the LNG concentration (100 nM) used in our study is comparable to that seen in the cervical secretions one month following LNG-IUD insertion 58 . This suggests that high concentrations of LNG in the FRT may not be detrimental to wound healing. ...
Mucosal integrity in the endometrium is essential for immune protection. Since breaches or injury to the epithelial barrier exposes underlying tissue and is hypothesized to increase infection risk, we determined whether endogenous progesterone or three exogenous progestins (medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG)) used by women as contraceptives interfere with wound closure of endometrial epithelial cells and fibroblasts in vitro. Progesterone and LNG had no inhibitory effect on wound closure by either epithelial cells or fibroblasts. MPA significantly impaired wound closure in both cell types and delayed the reestablishment of transepithelial resistance by epithelial cells. In contrast to MPA, NET selectively decreased wound closure by stromal fibroblasts but not epithelial cells. Following epithelial injury, MPA but not LNG or NET, blocked the injury-induced upregulation of HBD2, a broad-spectrum antimicrobial implicated in wound healing, but had no effect on the secretion of RANTES, CCL20 and SDF-1α. This study demonstrates that, unlike progesterone and LNG, MPA and NET may interfere with wound closure following injury in the endometrium, potentially conferring a higher risk of pathogen transmission. Our findings highlight the importance of evaluating progestins for their impact on wound repair at mucosal surfaces.
... nor DMPA use (aOR = 1.32, 95% CI 0. 42-4.16) was associated with detectable gVL in analysis adjusted for pVL. Our findings bear distinction from a mucosal immunology standpoint, as the LNG-IUS has markedly higher LNG concentrations in genital tract mucosa, reflecting its largely localized effect, in contrast to the LNG implant and DMPA [41]. When compared with the C-IUD, LNG does not appear to drive shedding via gVL; neither IUC appears to increase gVL through hypothesized inflammatory response from foreign body effect. ...
Background
Women living with HIV (WLHIV) have lower rates of contraceptive use than noninfected peers, yet concerns regarding contraceptive efficacy and interaction with antiretroviral therapy (ART) complicate counseling. Hormonal contraceptives may increase genital tract HIV viral load (gVL) and sexual transmission risk to male partners. We compared gVL, plasma VL (pVL), and intrauterine contraceptive (IUC) continuation between the levonorgestrel intrauterine system (LNG-IUS) and copper intrauterine device (C-IUD) in Cape Town, South Africa.
Methods and findings
In this double-masked, randomized controlled noninferiority trial, eligible WLHIV were ages 18–40, not pregnant or desiring pregnancy within 30 months, screened and treated (as indicated) for reproductive tract infections (RTIs) within 1 month of enrollment, and virologically suppressed using ART or above treatment threshold at enrollment (non-ART). Between October 2013, and December 2016, we randomized consenting women within ART groups, using 1:1 permuted block randomization stratified by ART use, age (18–23, 24–31, 32–40), and recent injectable progestin contraceptive (IPC) exposure, and provided the allocated IUC. At all visits, participants provided specimens for gVL (primary outcome), pVL, RTI, and pregnancy testing. We assessed gVL and pVL across 6 and 24 months controlling for enrollment measures, ART group, age, and RTI using generalized estimating equation and generalized linear models (non-ART group pVL and hemoglobin) in as-treated analyses. We measured IUC discontinuation rates with Kaplan-Meier estimates and Cox proportional hazards models. We enrolled 71 non-ART (36 LNG-IUS, 31 C-IUD; 2 declined and 2 were ineligible) and 134 ART-using (65 LNG-IUS, 67 C-IUD; 1 declined and 1 could not complete IUC insertion) women. Participant median age was 31 years, and 95% had 1 or more prior pregnancies. Proportions of women with detectable gVL were not significantly different comparing LNG-IUS to C-IUD across 6 (adjusted odds ratio [AOR]: 0.78, 95% confidence interval [CI] 0.44–1.38, p = 0.39) and 24 months (AOR: 1.03, 95% CI: 0.68–1.57, p = 0.88). Among ART users, proportions with detectable pVL were not significantly different at 6 (AOR = 0.83, 95% CI 0.37–1.86, p = 0.65) and 24 months (AOR = 0.94, 95% CI 0.49–1.81, p = 0.85), whereas among non-ART women, mean pVL was not significantly different at 6 months (−0.10 log10 copies/mL, 95% CI −0.29 to 0.10, p = 0.50) between LNG-IUS and C-IUD users. IUC continuation was 78% overall; C-IUD users experienced significantly higher expulsion (8% versus 1%, p = 0.02) and elective discontinuation (adjusted hazard ratio: 8.75, 95% CI 3.08–24.8, p < 0.001) rates. Sensitivity analysis adjusted for differential IUC discontinuation found similar gVL results. There were 39 serious adverse events (SAEs); SAEs believed to be directly related to IUC use (n = 7) comprised 3 pelvic inflammatory disease (PID) cases and 4 pregnancies with IUC in place with no discernible trend by IUC arm. Mean hemoglobin change was significantly higher among LNG-IUS users across 6 (0.57 g/dL, 95% CI 0.24–0.90; p < 0.001) and 24 months (0.71 g/dL, 95% CI 0.47–0.95; p < 0.001). Limitations included not achieving non-ART group sample size following change in ART treatment guidelines and truncated 24 months’ outcome data, as 17 women were not yet eligible for their 24-month visit at study closure. Also, a change in VL assay during the study may have caused some discrepancy in VL values because of different limits of detection.
Conclusions
In this study, we found that the LNG-IUS did not increase gVL or pVL and had low levels of contraceptive failure and associated PID compared with the C-IUD among WLHIV. LNG-IUS users were significantly more likely to continue IUC use and had higher hemoglobin levels over time. The LNG-IUS appears to be a safe contraceptive with regard to HIV disease and may be a highly acceptable option for WLHIV.
Trial registration
ClinicalTrials.gov NCT01721798.
Quantification of serum progestin levels in clinical contraceptive studies is now routinely performed to understand progestin pharmacokinetics and to correct for unreliable self-reporting of contraceptive use by study participants. Many such studies are focussed on the three-monthly progestin-only intramuscular (IM) injectable contraceptive depot medroxyprogesterone acetate (DMPA-IM). Methods commonly used to measure serum MPA levels include liquid chromatography coupled to mass spectrometry (LC/MS) and radioimmunoassay (RIA); however, RIA methods have not been used in recent years. We review the available literature and find that these methods vary widely in terms of use of organic solvent extraction, use of derivitization and choice of organic solvent and chromatography columns. There is a lack of standardization of LC/MS methodology, including a lack of detailed extraction protocols. Limited evidence suggests that RIA, without organic solvent extraction, likely over-estimates progestin levels. Maximum MPA concentrations in the first two weeks post-injection show wide inter-individual and inter-study variation, regardless of quantification method used. Standardization of quantification methods and sampling time post-injection is required to improve interpretation of clinical data, in particular the side effects arising at different times depending on the pharmacokinetic profile unique to injectable contraceptives.
Many different forms of hormonal contraception are used by millions of women worldwide. These contraceptives differ in the dose and type of synthetic progestogenic compound (progestin) used, as well as the route of administration and whether or not they contain estrogenic compounds. There is an increasing awareness that different forms of contraception and different progestins have different side-effect profiles, in particular their cardiovascular effects, effects on reproductive cancers and susceptibility to infectious diseases. There is a need to develop new methods to suit different needs and with minimal risks, especially in under-resourced areas. This requires a better understanding of the pharmacokinetics, metabolism, serum and tissue concentrations of progestins used in contraception as well as the biological activities of progestins and their metabolites via steroid receptors. Here we review the current knowledge on these topics and identify the research gaps. We show that there is a paucity of research on most of these topics for most progestins. We find that major impediments to clear conclusions on these topics include a lack of standardized methodologies, comparisons between non-parallel clinical studies and variability of data on serum concentrations between and within studies. The latter is most likely due, at least in part, to differences in intrinsic characteristics of participants. The review highlights the importance of insight on these topics in order to provide the best contraceptive options to women with minimal risks.
Millions of women are exposed simultaneously to antiretroviral drugs (ARVs) and progestin-based hormonal contraceptives. Yet, the reciprocal modulation by ARVs and progestins of their intracellular functions is relatively unexplored. We investigated the effects of tenofovir disoproxil fumarate (TDF) and dapivirine (DPV), alone and in the presence of select steroids and progestins, on cell viability, steroid-regulated immunomodulatory gene expression, activation of steroid receptors and anti-HIV-1 activity in vitro . Both TDF and DPV modulated the transcriptional efficacy of a glucocorticoid agonist via the glucocorticoid receptor (GR) in the U2OS cell line. In TZM-bl cells, DPV induced the expression of the pro-inflammatory interleukin (IL)-8 gene while TDF significantly increased medroxyprogesterone acetate (MPA)-induced expression of the anti-inflammatory glucocorticoid-induced leucine zipper (GILZ) gene. However, peripheral blood mononuclear cell (PBMC) and ectocervical explant cell viability and gene expression results along with TZM-bl HIV-1 infection data are reassuring and suggest that TDF and DPV, in combination with dexamethasone (DEX) or MPA, do not reciprocally modulate key biological effects in primary cells and tissue. However, we show for the first time that TDF induces progestogen-independent activation of the progesterone receptor (PR) in a cell line. The capacity of TDF and DPV to influence GR and PR activity suggests that their use may be associated with steroid receptor-mediated off-target effects. This, together with cell line and individual donor gene expression responses in the primary models, raises concerns that reciprocal modulation may cause side-effects in a cell- and donor-specific manner in vivo .
